The effects of desipramine, zimelidine, electroconvulsive treatment and lithium on rat brain biogenic amines: a comparison with peripheral changes

The effects of 4 common treatments for affective disorders on total body norepinephrine (NE) and dopamine (DA) turnover and metabolism were evaluated in rats. The treatments were chronic desipramine (DMI), zimelidine (ZMI), electroconvulsion (ECT) and lithium (Li). The central effects of ECT and Li were also assessed in the brain. The results obtained were compared with the effects of these 4 treatments on total NE (Sum NE) and DA (Sum DA) turnover in depressed patients. We have also evaluated central and/or peripheral effects of these treatments on phenylethylamine, p-tyramine and serotonin metabolism. The urinary changes in Sum NE and DA observed after DMI, ZMI and Li in the rat were similar to those found in depressed patients; Sum NE was significantly reduced. In contrast to its effects on depressed patients, chronic ECT significantly increased Sum NE. Similar to depressed patients, ECT reduced the fraction of NE escaping re-uptake in the rat. Sum DA was not affected by DMI, ZMI or ECT, but was significantly reduced by chronic Li treatment. All 4 treatments significantly reduced serotonin metabolism as indicated by reduced 5-hydroxyindoleacetic acid excretion rates. DMI, ZMI and Li treatments significantly reduced phenylethylamine urinary but not p-tyramine urinary outputs. The opposite effect was observed after ECT. Consistent with their effects on Sum NE, Li reduced while ECT increased hypothalamic NE turnover as deduced from the changes in 3-methoxy-4-hydroxyphenylglycol's rate of formation. As for Sum DA, Li had no effect on 3,4-dihydroxyphenylacetic acid or homovanillic acid's rates of formation in the caudate nucleus. Chronic ECT produced a small, but significant increase in homovanillic acid's rate of formation in the caudate nucleus.     

Effects of prolonged administration of milnacipran, a new antidepressant, on receptors and monoamine uptake in the brain of the rat.

Most antidepressants produce changes in monoamine receptors in brain after chronic administration in animals. The most commonly described alterations are a decreased density and function of beta-adrenergic receptors and have been postulated to be the mechanisms by which antidepressants exert their therapeutic effect. Milnacipran (previous name midalcipran) is a new, clinically-effective antidepressant, which inhibits the uptake of both serotonin and noradrenaline but has no affinity for any pre- or postsynaptic receptor studied. When given either orally at 7.5 mg/kg twice daily for 3 days, at 30 mg/kg once daily for 3 weeks, by osmotic mini-pump at 30 mg/kg/day for 27 days, or in drinking water at approximately 15 mg/kg/day for 6 weeks and after a washout period of 24 hr, milnacipran produced no down-regulation of beta-adrenoceptors. In addition, there were no alterations of alpha 1- or alpha 2-adrenoceptors, 5-HT1, 5-HT2 receptors or benzodiazepine binding sites. Moreover, uptake and accumulation of serotonin and noradrenaline were unmodified. In addition, the potency for milnacipran to inhibit monoamine uptake in vitro in the cortex was not altered in treated rats, compared to control animals. Thus, in spite of its action on both the uptake of serotonin and noradrenaline, milnacipran appears to be without long-term action on beta-adrenoceptors or the other receptors studied, suggesting that, at least for this antidepressant, these modifications are not essential for clinical activity.     

Effect of acute and chronic treatment of tandamine,a new heterocyclic antidepressant,on biogenic amine metabolism and related activities

Summary The effects of tandamine, a clinically effective heterocyclic antidepressant, administered either acutely (10 mg/kg i.p) or chronically (10 mg/kg i.p. daily for 21 days) on biogenic amine uptake and metabolism in the rat were determined and a comparison with desipramine was made. Tandamine, similarly to desipramine, blocked norepinephrine (NE) uptake in rat brain and heart following both acute and chronic administration. No effect of tandamine on dopamine (DA) or serotonin (5-HT) uptake was observed. Both drugs lowered endogenous brain NE when given chronically but not acutely. In contrast, no such effect on brain DA and 5-HT or heart NE was observed. Tandamine, like desipramine, administered chronically prior to an intraventricular injection of ³H-NE, produced increases in the decline of ³H-NE as indicated by decreased ³H-NE with increased levels of ³H-normetanephrine in brain stem of rats, suggesting an increased turnover of NE. No such effect was observed following acute treatment. Both drugs increased the behavioural effects of L-Dopa following an acute oral administration, with tandamine appearing superior to desipramine at the lower dose examined (10 mg/kg). Tandamine was 57–833 times less effective in binding to rat brain muscarinic receptors than desipramine, imipramine, butriptyline and amitriptyline, respectively. Thus, tandamine affects biogenic amine mechanism following either acute or chronic administration in a fashion similar to desipramine, but unlike desipramine, it exhibits relatively little anticholinergic properties, a further indication of the potential use of tandamine in the treatment of human depression, particularly where an increase in drive is desired.     

The effects of tandamine, a new potential antidepressant agent, on biogenic amine uptake mechanisms and related activities.

The effects of various thiopyrano [3,4-b]indoles and pyrano [3,4-b] indoles on norepinephrine (NE) and 5-hydroxytryptamine (5-HT) uptake were determined in mice. A thiopyranoindole, tandamine,¹ was a potent inhibitor of [³H]NE uptake in the heart, being three times more active than desimipramine, and was relatively ineffective in potentiating the 5-hydroxytryptophan (5-HTP) behavioural syndrome. A pyranoindole and a thiopyranoindole blocked both [³H]NE and brain 5-HT uptake with activities greater than, or similar to imipramine. Structure-activity relationships for these two activities were determined. Tandamine was the most potent in antagonizing reserpine-induced hypothermia and the guanethidine-induced depletion of heart [³H]NE. The (?)enantiomer of tandamine exhibited greater activity in blocking NE and 5-HT uptake. The results indicate that tandamine and certain, of its congeners, differing chemically from the known tricyclic antidepressants, exert relatively selective stereochemical effects on NE and 5-HT uptake mechanisms. Such agents are potentially useful as antidepressants and as tools for further studies of the uptake mechanism and functional significance of NE and 5-HT.     

Protein kinase C in rat brain cortex and hippocampus: effect of repeated administration of fluoxetine and desipramine.

1. Recent evidence indicates that changes in the activity of cyclic AMP-dependent protein kinase may be involved in neuroadaptive mechanisms after chronic treatment with antidepressants. The aim of this study was to investigate the effect of repeated administration of fluoxetine (FL) and desipramine (DMI) on the distribution and activity of protein kinase C (PKC) in subcellular fractions of rat cortex (Cx) and hippocampus (Hc) under basal conditions and in response to a single in vivo administration of 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). 2. Rats were treated for 21 days with FL (5 mg kg-1 day-1, i.p.) or DMI (10 mg kg-1 day-1, i.p.). DOI was injected to groups of rats receiving repeated doses of antidepressants or to control rats 1 h before ex vivo PKC assay. Distribution of PKC was determined by [3H]-phorbol-12,13-dibutyrate ([3H]-PDBu) binding and PKC activity by the Amersham enzyme assay system. 3. Autoradiography of tissue sections revealed decreased [3H]-PDBu binding in CA1 region of hippocampus (by 18%) and paraventricular thalamic nucleus (by 28%) of rats after repeated administration of FL. 4. In vitro exposure of brain sections to 50 microM FL resulted in significant decreases (by 23-32%) of [3H]-PDBu binding in six out of seven regions examined; exposure to 100 microM FL reduced [3H]-PDBu binding (by 36-52%) in all regions. In contrast, exposure of brain sections to 100 microM DMI failed to alter specific [3H]-PDBu binding in brain sections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of chronic monoamine oxidase inhibitor treatment on biogenic amine metabolism in rat brain.

The effects of acute and chronic administration of phenelzine and tranylcypromine on rat brain monoamine metabolism have been examined. Peak increases in norepinephrine, dopamine and 5-hydroxytryptamine occurred between 1 and 7 days with monoamine oxidase inhibitor treatments followed by a gradual decline in brain monoamines towards control levels with continued chronic drug administration. There was an associated adaptive increase in tryptophan hydroxylase but no change in tyrosine hydroxylase activity with chronic phenelzine treatment. Tranylcypromine did not affect tryptophan hydroxylase or tyrosine hydroxylase activities but was associated with a significant increase in aromatic amino acid decarboxylase activity after 14 and 21 days of treatment.     

Influence of the antidepressant binodaline on biogenic amine uptake and brain levels in the rat

The influence of 1-(omega-dimethylaminoethylmethyl)-amino-3-phenylindole hydrochloride (binodaline, Sgd-Scha 1059) on the uptake of noradrenaline (norepinephrine, NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) into pre-synaptic nerve endings has been studied using purified synaptosomal preparations from various regions of rat brain. Binodaline was found to be an effective inhibitor of biogenic amine uptake the IC50 values being 5.0 X 10(-6) mol/l (NA), 2.3 X 10(-7) mol/l (5-HT) and 1.5 X 10(-6) mol/l (DA). The desmethyl analogue of binodaline (Sgd 20578) also inhibited transmitter uptake into cerebral nerve endings, being more potent than the parent compound in inhibiting NA uptake (8.5 X 10 mol/l), of a similar potency with respect to 5-HT (3.2 X 10(-7) mol/l) and slightly less potent against DA (8.3 X 10(-6) mol/l). Neither binodaline nor the desmethyl derivative was found to influence cerebral levels of NA, 5-HT and DA following acute dosing in rats. Brain concentrations of the related metabolites 5-hydroxyindolacetic acid, dihydroxyphenylacetic acid and homovanillinic acid were also unchanged. It is concluded that binodaline owes its antidepressant activity at least in part to its ability to inhibit monoamine uptake into pre-synaptic cerebral nerve endings.     

Effects of lithium and desipramine administration on agonist-stimulated inositol phosphate accumulation in rat cerebral cortex

The effects of acute lithium and chronic desipramine administration on the inositol phosphate responses of rat cerebral cortical slices to noradrenaline, carbachol and 5-hydroxytryptamine, were determined. Acute injection of lithium (4 meq/kg s.c. 24 hr before sacrifice) significantly increased the inositol-1-phosphate response to noradrenaline, while chronic administration of desipramine (10 mg/kg i.p. for 3 weeks) produced a smaller increase in this parameter. Chronic desipramine also decreased the serotonin responses in terms of all three inositol phosphates measured. No potentiative or additive interactions between the lithium and desipramine effects were observed.     

Effects of repeated zimelidine administration on sleep parameters in the rat

The purpose of this study was to determine if non-pharmacological stimuli influence behavioral tolerance to haloperidol via striatal postsynaptic dopamine receptors. Rats received daily haloperidol and saline in two different environments for a period of 28 days. After this conditioning period half of the rats received haloperidol in the haloperidol-associated environment, whereas the other half received haloperidol in the saline-associated environment. All rats were tested for catalepsy and at the end of the last catalepsy test, striatal DOPAC, HVA and ACh were determined. Only the rats tested in the haloperidol-associated environment were behaviourally tolerant to haloperidol. In contrast, both groups were biochemically tolerant to haloperidol.These results indicate that environmental cue factors govern the development of behavioural tolerance to haloperidol, rather than biochemical factors (striatal DA supersensitivity). In addition, these factors do not exert their influence on behavioural tolerance via striatal DA receptors.     

Effects of acute and chronic treatment with an atypical antidepressant drug,nomifensine, on the sleep-wake activity in rats

After the chronic administration of saline, rats were treated with nomifensine (0.1 or 1.0 mg/kg, twice a day, at light and dark onset) for 11 days. The sleep-wake activity was recorded for 24 h on the baseline day (saline), on nomifensine days 1, 5 and 11, and also on day 12, when saline was injected again (withdrawal day). Another group of rats was treated with saline throughout the experiment, without significant effect on the sleep-wake activity. The smaller dose of nomifensine increased non-REM sleep (NREMS) at the expense of wakefulness (W) in the light period. The effect persisted throughout the chronic treatment. A late increase in REM sleep (REMS) was noted on nomifensine days 5 and 11. Nomifensine failed to affect the sleep-wake activity in the dark period. On withdrawal, the baseline percentages of the vigilance states were recovered. As evaluated through spectral analysis of the EEG, the increase in NREMS was accompanied by an increase in slow wave activity. The higher dose of nomifensine elicited an increase in W and a reduction in both sleep states, followed by changes in W and NREMS in the opposite directions. These effects were evident in both the light and the dark periods of the day. Chronic treatment resulted in circadian variations in the effects. Withdrawal of the drug abolished the arousal reaction, but the late increase in NREMS persisted. The dose-dependent biphasic effects of nomifensine on sleep-wake activity can be explained by considering the proposed indirect dopamine and possibly noradrenaline agonist activity of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of ginsenoside Rg1 in rat medial prefrontal cortex,hippocampus, and lateral ventricle after subcutaneous administration

The present study aimed to investigate pharmacokinetics of Rg1 in rat medial prefrontal cortex (mPFC), hippocampus (HIP), and lateral ventricle (LV) after subcutaneous injection. For the first time, intracerebral pharmacokinetics of Rg1 was studied in freely moving rats by microdialysis technique. Rg1 concentrations in dialysates were detected by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method and were revised using in vivo probe-recovery in HIP and LV. The pharmacokinetic parameters were then determined using non-compartmental models. Since the in vivo recoveries remained stable in HIP and LV during 9 h dialysis, average recoveries were used to revise dialysate concentrations. After dosing, Rg1 was soon detected in brain extracellular fluid (bECF) and cerebrospinal fluid (CSF). The elimination of Rg1 was significantly slower in mPFC than in HIP and LV, and significantly greater AUC was obtained in mPFC than in HIP. Rg1 kinetics in bECF and CSF indicate that Rg1 can go across the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), and then immediately distribute to learning and memory-related regions in brain, which may lead to rapid pharmacological onset. There may be active transport and target-mediated disposition of Rg1 in the CNS, which need to be further clarified.     

Effect of antidepressant drugs on veratridine-evoked glutamate and aspartate release in rat prefrontal cortex.

In vivo microdialysis in conscious rats was used to evaluate the effect of local application, through a microdialysis probe, of desipramine (DMI), imipramine and citalopram (CIT), on veratridine-evoked glutamate and aspartate release in rat prefrontal cortex (PFCx). All antidepressant drugs (ADs), given at a concentration of 0.1 mM, significantly inhibited glutamate release, while aspartate release was affected only by DMI and CIT. In contrast, local administration of ADs markedly potentiated veratridine-evoked dopamine and noradrenaline release. Perfusion of clonidine, quinpirole and 1-[3-(trifluoro-methyl)phenyl]-piperazine (TFMPP) at 0.1 mM concentration also diminished, evoked release of glutamate and aspartate. The regulation of amino acid release in rat PFCx may be achieved by direct effect of ADs on Na+ channels or indirectly, by involvement of D2/D3, alpha 2 or 5-HT1B heteroceptors activated by the increased level of monoamines in response to the blockade of respective transporters.     

Reduced activation of intracellular signaling pathways in rat prefrontal cortex after chronic phencyclidine administration.

Evidence exists that schizophrenia is characterized by deficits in cell-cell communication and information processing. In the present study, we used the phencyclidine (PCP) animal model of schizophrenia to investigate possible defects in intracellular signaling proteins involved in neuroplasticity. Western Blot analysis has been performed to determine total and phospho-protein levels of extracellular signal-regulated kinases 1/2 (ERK1/2), type II calcium/calmodulin-dependent protein kinase (alphaCaMKII) and cAMP-response element binding protein (CREB) in prefrontal cortex (PFC) and hippocampus (HIP) of rat chronically treated with PCP, whereas their mRNA levels were determined by real time RT-PCR. We found reduced levels of P-ERK1/2, P-alphaCaMKII and P-CREB in prefrontal cortex of PCP-treated animals when compared to controls, whereas no effects were observed on total protein or mRNA levels. Conversely, no significant changes were detected on protein levels or mRNA expression in hippocampus. Given the role of ERK1/2, alphaCaMKII and CREB in neuroplastic mechanisms and cell communication, our data suggest that their decreased activation following chronic PCP administration can contribute to cortical defects occurring in schizophrenia, and may therefore represent potential targets for pharmacological intervention.     

Reduced metabolism and turnover rates of rat brain dopamine, norepinephrine and serotonin by chronic desipramine and zimelidine treatments

As part of of an ongoing effort to compare changes in whole body turnover of catecholamines and serotonin in man with those induced by antidepressants in the rat brain, we have evaluated the chronic effects of desipramine (DMI) and zimelidine (ZMI) on brain catecholamines and serotonin in the rat. The amines and metabolites measured include norepinephrine (NE), dopamine (DA) and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Three brain areas were analysed; the hypothalamus, caudate nucleus and frontal cortex. Chronic DMI and ZMI reduced hypothalamic MHPG and caudate nucleus DA metabolites, in particular HVA. Both drugs reduced NE and DA turnover rates (estimated after alpha-methyl-p-tyrosine injection) and the rate of MHPG formation in the hypothalamus (estimated after pargyline treatment). They did not change NE turnover rate, but reduced DA turnover rate and rate of HVA formation in the caudate nucleus. Chronic DMI but not ZMI reduced DOPAC rate of formation in the caudate nucleus. Apparently changes in DA turnover and metabolism produced by these antidepressants are better related to changes in HVA than DOPAC concentrations. Similar to their influence on hypothalamic and caudate nucleus catecholamines, both chronic DMI and ZMI produced changes in serotonin concentration in the caudate nucleus and frontal cortex serotonin that suggest a reduction in its turnover rate and metabolism. The reduction in NE turnover in hypothalamus is consistent with the effects of chronic DMI and ZMI on whole body NE turnover observed in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic administration of desipramine and zimelidine changes the behavioural response in the formalin test in rats.

In studies of the effect on nociception of chronic administration of antidepressants, the stress of the injections may influence the results. In this experiment, desipramine or zimelidine were administered in the drinking water of rats, in a concentration yielding a dose of approximately 8 mg/kg/24 hr. Desipramine, given both for a short time (24 hr) and chronically (14 days), induced antinociception in the increasing temperature hot-plate test; zimelidine did not significantly influence the results of this test. In the tail-flick test, neither short-term nor chronic administration of these antidepressants had any effect on nociception, when correction was made for the changes in the temperature of the tail skin. In the formalin test, nine behavioural categories were scored for 1 hr and the data were treated statistically, using a multivariate analysis. Chronic administration of desipramine increased nociceptive behaviour during the first 10 min of the test. Desipramine and, to a lesser extent, zimelidine, changed the response in the late phase (10-60 min), showing less focussed pain-related behaviour (jerks and shaking, licking and biting of the injected paw) and more non-focussed pain-related behaviour (activity states with elevation or protection of the injected paw). It was concluded that desipramine is antinociceptive in the increasing temperature hot-plate test. Desipramine and zimelidine, administered chronically, modify the late phase of the formalin test towards less focussed pain-related behaviour, suggesting an antinociceptive effect. Multivariate analysis of the data of the formalin test seemed to be of value for the interpretation of the data.     

Effect of acute and chronic administration of citalopram on glutamate and aspartate release in the rat prefrontal cortex

The present study was designed to determine whether peripheral administration of the selective serotonin reuptake inhibitor (SSRI) citalopram influenced glutamate and aspartate release in the rat prefrontal cortex using in vivo microdialysis. Citalopram was given acutely at doses of 10 and 20 mg/kg or chronically at a dose of 10 mg/kg daily for two weeks, in both cases by intraperitoneal (ip) route. Citalopram given at a single dose of 20 mg/kg, but not 10 mg/kg, significantly inhibited release of glutamate and aspartate induced by sodium channel activator, veratridine (100 microM). Glutamate and aspartate release was also diminished in animals treated chronically with citalopram. Citalopram did not affect extracellular level of 5-hydroxytryptamine (5-HT) after acute doses, but increased it after chronic administration. On the other hand, single and repeated doses of the drug inhibited veratridine-evoked 5-HT release. Neither single nor chronic treatment with citalopram influenced spontaneous and evoked dopamine (DA) release. The results suggest that in the presence of depolarizing agent, e.g. under conditions resembling a disturbed homeostasis of neuronal network, antidepressant drugs with profile of SSRI may influence excitatory systems in the brain. This effect does not seem to be dependent on the interaction with 5-HT or DA neurotransmission, but rather some inhibitory modulators stimulated in stress situations may contribute to the observed results.     

Effects of chronic oral administration of the antidepressants, desmethylimipramine and zimelidine on rat cortical GABAB binding sites: a comparison with 5-HT2 binding site changes.

1. The effects of chronic oral administration of desmethylimipramine (DMI) or zimelidine (1.25 and 5 mg kg-1 twice daily for 21 days) were studied on rat whole cortical gamma-aminobutyric acidB (GABAB) binding sites. No changes in receptor affinity or number were found with either drug. 2. A subsequent study of GABAB binding sites using higher doses of these drugs (5 and 10 mg kg-1) and rat frontal cortex was also without effect, when investigated 24 h after termination of drug administration or 72 h after DMI administration (5 mg kg-1). 3. The number of frontal cortical 5-hydroxytryptamine2 (5-HT2) binding sites was significantly and dose-dependently decreased after both drugs, whereas the number of hippocampal 5-HT2 binding sites was not significantly altered after either drug. 4. As the number of frontal cortical GABAB binding sites was unaltered whereas the number of 5-HT2 binding sites was significantly decreased under identical study conditions, it may be concluded that the effects of antidepressant administration upon GABAB binding sites is a less consistent observation than their effects on 5-HT2 binding sites.     

Organ-specific, qualitative changes in the phospholipid composition of rats after chronic administration of the antidepressant drug desipramine

Rats were chronically treated with daily i.p. injections of 10 mg/kg desipramine for 21 days. A 30% decrease in the number of beta-adrenoceptors was observed in brain. A receptor desensitization of similar extent was noted in submaxillary glands and lung. No change in beta-adrenoceptor number was present in heart. Total phospholipid contents were not altered in these organs after chronic drug treatment. However, organ-specific changes were found in the phospholipid composition of submaxillary glands, lung and liver but not in whole brain and heart. The changes were variable but an increase in phosphatidylinositol and decreases in phosphatidylethanolamine and sphingomyelin were consistent. Possible alterations in the phospholipid composition of the brain might have been masked by the large and stable pool of myelin phospholipids. A casual relationship between changes in the phospholipid composition and beta-adrenoceptor desensitization is discussed.